GPR124 functions as a WNT7-specific coactivator of canonical ?-catenin signaling.

ABSTRACT: G protein-coupled receptor 124 (GPR124) is an orphan receptor in the adhesion family of GPCRs, and previous global or endothelial-specific disruption of Gpr124 in mice led to defective CNS angiogenesis and blood-brain barriergenesis. Similar developmental defects were observed following dual deletion of Wnt7a/Wnt7b or deletion of ?-catenin in endothelial cells, suggesting a possible relationship between GPR124 and canonical WNT signaling. Here, we show using in vitro reporter assays, mutation analysis, and genetic interaction studies in vivo that GPR124 functions as a WNT7A/WNT7B-specific costimulator of ?-catenin signaling in brain endothelium. WNT7-stimulated ?-catenin signaling was dependent upon GPR124's intracellular PDZ binding motif and a set of leucine-rich repeats in its extracellular domain. This study reveals a vital role for GPR124 in potentiation of WNT7-induced canonical ?-catenin signaling with important implications for understanding and manipulating CNS-specific angiogenesis and blood-brain barrier-genesis.

SUBMITTER: Posokhova E 

PROVIDER: S-EPMC4331012 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature